Recent Advances in the Molecular Mechanisms of Bacterial Anti-Phage Defence Systems

Deep learning models based on both distant protein sequence homology and genetic neighbourhood context searches predicted that 1.5% of bacterial genes or 30 genes per E. coli genome represent anti-phage systems (APS); many are colocalized on defence islands or are found on mobile DNA elements. Thousands of APS thus remain to be defined molecularly. Selected recent examples highlighting an astonishing molecular diversity of these defence systems are described in this editorial. The mechanisms include allosterically regulated dGTPase responding to competing nucleotide signals (Clover); bacterial defence systems activated by phage anti-defence manoeuvres (Panoptes); a prophage encoded tRNA nuclease activated by a phage tail tip protein (HepS); a helicase-nuclease complex that scans for ssDNA 3' overhangs created by phage DNA transaction (Hachiman); and systems that cleave free ends of linear DNA (Shedu). Systems were described that synthesize template-free poly-dA chains which are degraded by a phage exonuclease thereby activating an ion channel (Hailong). Several systems interfere with phage DNA injection into the cell, for example, a cell membrane associated protein complex inhibiting injection (KIWA); or destroying phage DNA at injection (SNIPE); or a complex membrane motor system that senses phage DNA injection and activates nuclease effectors (Zorya). Other systems consist of a single pore building protein that combines sensor and effector functions (Rip1) or degrade NAD⁺ (Cat1). Defence-associated reverse transcriptase (DRT) preceded by non-coding RNA (ncRNA) come in different forms: in DRT2 a rolling circle reverse transcription leads to an endless protein inducing cell dormancy; in DRT3 a mixed templated and untemplated repeat DNA synthesis becomes cytotoxic in presence of a phage protein; DRT9 synthesizes a polyA strand that might sequester a phage protein needed for DNA replication. Striking are bacterial APS that resemble innate immune reaction directed against viruses in animals (gasdermin, Argonaute, RAZR, Schlafen, Thoeris 2, ubiquitin-like proteins) pointing to an ancient origin.